Dispersible bosentan tablet

ABSTRACT

The invention relates to dispersible tablets comprising the compound 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulfonamide.

The present invention relates to dispersible tablets comprising thecompound4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]-benzenesulfonamide,said compound being hereinafter referred to as compound I.

Compound I has the following formula:

Compound I is an endothelin receptor inhibitor and useful for thetreatment of pulmonary arterial hypertension (PAH). Compound I and thepreparation thereof is disclosed in EP to 0526708 A1.

Bosentan (Tracleer®) is an oral treatment for PAH (Class III and IV inthe United States, Class III in Europe). Bosentan is a dual endothelinreceptor antagonist with affinity for both endothelin ETA and ETBreceptors thereby preventing the deleterious effects of ET-1. As knownfrom the World Standard Drug Database, the commercial availableformulation has the following composition: bosentan (125 or 62.5 mg),starch, triacetin, magnesium stearate, talc, ferric oxide, povidone,titanium dioxide, ethylcellulose, glyceryl behenate, hypromellose andsodium starch glycollate.

Within the context of this disclosure, any reference to compound I is tobe understood as referring also to pharmaceutically acceptable salts orsolvates, including hydrates, of Compound I, as well as morphologicalforms thereof, if not indicated otherwise and where appropriate andexpedient.

By “dispersible tablet” is meant a tablet, which disintegratescompletely in water at 15-22° C. in not more than 5 minutes orpreferably less than 4 minutes. In a further embodiment the dispersibletablets of the present invention have a disintegration time of less than3 minutes, preferably less than 2 minutes or most preferred less than 1minute (disintegration method according to the European Pharmacopoeia,EP).

The present drug product of compound I is currently being marketed as atablet for the treatment of PAH, a deadly disease if untreated. Childrenhave difficulties in taking tablets, thus the currently marketed tabletformulation is not convenient for administration to children. A drugproduct in the form of a suspension will be more children-friendly. Thepresent invention therefore relates to the development of a tablet,which can be dispersed in water to form a suspension beforeadministration. The dispersible tablet should disintegrate completely inwater at 15-22° C. in less than 5 minutes or preferably less than 4minutes. In a further embodiment the dispersible tablets of the presentinvention have a disintegration time of less than 3 minutes, preferablyless than 2 minutes or most preferred less than 1 minute based on themethod according to the European Pharmacopoeia (disintegration methodaccording to the EP).

Further advantages of the paediatric formulation are the following:

-   -   Better compliance due to special paediatric formulation    -   It is now possible to give paediatric patients an optimized and        individualized dosing according to body weight    -   The paediatric formulation has demonstrated absorption based on        pk data

The present invention provides such a dispersible tablet suitable forchildren comprising: (a) compound I and (b) pharmaceutically acceptableexcipients suitable for the preparation of dispersible tablets. Theamount of compound I, calculated as the percentage of the content inweight of the active moiety, based on the total weight of thedispersible tablet, is 5% to 40%, preferably between 8% to 30%. Inparticular, the amount of compound I as active ingredient may vary from10% to 17%.

In a preferred embodiment of the invention, the present inventionprovides a dispersible tablet wherein compound I is in the monohydrateform.

One or more pharmaceutically acceptable excipients may be present in thedispersible tablet, e.g. fillers (1.1), disintegrants (1.2), glidants(1.3), acidifying agents (1.4), flavouring agents (1.5), sweeteningagents (1.6), and lubricants (1.7).

Reference is made to the extensive literature on the subject for theseand other pharmaceutically acceptable excipients and proceduresmentioned herein, see in particular Handbook of PharmaceuticalExcipients, Third Edition, edited by Arthur H. Kibbe, AmericanPharmaceutical Association, Washington, USA and Pharmaceutical Press,London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik andangrenzende Gebiete edited by H. P. Fiedler, 4th Edition, Edito Cantor,Aulendorf and earlier editions.

Fillers (1.1) according to the invention include but are not restrictedto microcrystalline cellulose, dicalcium phosphate, lactose andpregelatinized starch. Preferably, microcrystalline cellulose is used incombination with dicalcium phosphate.

Suitable disintegrants (1.2) according to the invention include but arenot restricted to croscarmellose sodium, sodium starch glycolate, maizestarch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PVP,e.g. as known and commercially available under the trade namesCrospovidone, Polyplasdone, available commercially from the TSP company,or Kollidon® XL, alginic acid, sodium alginate, pregelatinized starch,and guar gum. Preferably, Croscarmellose sodium, e.g. Ac-Di-Sol® isused.

As glidants (1.3), one or more of the following may be used: silica;colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil® 200,magnesium trisilicate, powdered cellulose, starch and talc. Preferably,colloidal silicone dioxide is used.

Acidifying agents (1.4) include but are not restricted to tartaric acid,citric acid, ascorbic acid, lactic acid, and fumaric acid. Preferablytartaric acid is used

Flavouring agents (1.5) include but are not restricted to Tutti Frutti,Strawberry, Banana, and Vanilla. Preferably Tutti Frutti is used.

Appropriate sweetening agents (1.6) according to the invention includebut are not restricted to: Aspartame, acesulfame potassium, saccharin,saccharin sodium, sodium cyclamate, sucralose. Preferably the sweeteningagents used are aspartame and acesulfame potassium.

Added flavouring agents as mentioned above and/or sweetening agents asmentioned above have the advantage to increase the compliance.

As lubricants (1.7) one or more of the following may be used Mg-, Al- orCa-stearate, stearic acid, sodium stearyl fumarate, talc, sodiumbenzoate, glyceryl mono fatty acid, e.g. having a molecular weight offrom 200 to 800 Daltons, e.g. glyceryl monostearate (e.g. Danisco, UK),glyceryl dibehenate (e.g. CompritolAT0888™, Gattefossé France), glycerylpalmito-stearic ester (e.g. Precirol™, Gattefossé France), polyethyleneglycol (PEG, BASF), hydrogenated cotton seed oil (Lubitab, EdwardMendell Co Inc.), castor seed oil (Cutina H R, Henkel) and sucroseesters (Surfhope S E, Mitsubishi-Kagaku Foods Co.). Preferably,magnesium stearate, alone or in combination with glyceryl dibehenate, isused.

It will be appreciated that any given excipient may serve more than onefunction e.g. as filler, disintegrant, binder, glidant, and/orlubricant.

In a preferred embodiment, the dispersible tablet comprises thefollowing pharmaceutically acceptable excipients: a) at least one filler(1.1) and b) at least one lubricant (1.7).

In another preferred embodiment, the dispersible tablet comprises thefollowing pharmaceutically acceptable excipients: a) at least one filler(1.1), b) at least one lubricant (1.7) and c) at least one disintegrant(1.2).

It was found that the presence of an acidifying agent (1.4) decreasesthe solubility of compound I thus preventing tasting of the bitter tasteof compound I when the tablet is dispersed with water e.g. on a spoonbefore administration. The bitter taste of compound I can also beovercome by using flavouring agents (1.5) and/or sweetening agents(1.6).

In one embodiment of the invention, the dispersible therefore comprisesthe following pharmaceutically acceptable excipients: at least oneacidifying agent (1.4) and/or at least one flavouring agent (1.5) and/orat least one sweetening agent (1.6), preferably together with at leastone filler (1.1) and at least one lubricant (1.7), preferablyadditionally comprising at least one disintegrant (1.2) and optionallyalso comprising at least one glidant (1.3).

According to the present invention, the amount of filler (1.1) may varywithin a range of 40 to 85%, in particular 63 to 78% in weight based onthe total weight of the dispersible tablet.

The amount of disintegrant (1.2) may vary within a range of from 0.5 to20%, e.g. 1 to 15% in weight based on the total weight of thedispersible tablet.

The amount of glidant (1.3) may vary within ranges of from 0.1 to 5%, inparticular 0.1 to 2.5%, especially 0.5 to 1.0% in weight based on thetotal weight of the dispersible tablet.

The amount of acidifying agent (1.4) may vary within ranges of from 0.5to 13%, in particular 1 to 8% in weight based on the total weight of thedispersible tablet.

The amount of flavouring agent (1.5) may vary from 1 to 15%, preferablyfrom 2 to 10% in weight based on the total weight of the dispersibletablet.

The amount of sweetening agent (1.6) may vary from 0.1 to 10%,preferably from 0.2 to 8%.

The amount of lubricant (1.7) may vary from 0.05 to 7%, preferably from0.1 to 3.0%.

In a preferred aspect of the invention, the dispersible tablet comprisesthe following pharmaceutically acceptable excipients: one or morefillers (1.1), especially in a total amount of 40 to 85%, preferablyfrom 63% to 78%, in weight based on the total weight of the dispersibletablet, one or more disintegrants (1.2), especially in a total amount of0.5 to 20%, preferably from 1% to 15%, in weight based on the totalweight of the dispersible tablet, one or more glidants (1.3), especiallyin a total amount of 0.1 to 5%, preferably from 0.5% to 1.0%, in weightbased on the total weight of the dispersible tablet, one or moreacidifying agents (1.4), especially in a total amount of 0.5 to 13%,preferably from 1% to 8%, in weight based on the total weight of thedispersible tablet, one or more flavouring agents (1.5), especially in atotal amount of 1 to 15%, preferably from 2% to 10%, in weight based onthe total weight of the dispersible tablet, one or more sweeteningagents (1.6), especially in a total amount of 0.1 to 10%, preferablyfrom 0.2 to 8%, in weight based on the total weight of the dispersibletablet, and one or more lubricants (1.7), especially in a total amountof 0.05 to 7%, preferably from 0.1% to 3.0%, in weight based on thetotal weight of the dispersible tablet.

The absolute amounts of each pharmaceutically acceptable excipient andthe amounts relative to other pharmaceutically acceptable excipients isdependent on the desired properties of the dispersible tablet and may bechosen by routine experimentation.

The tablets of the invention are dispersible, e.g. in aqueous media suchas water. The tablets can thus be dispersed in e.g. water beforeadministration, which is a convenient form of administration forchildren. This also leads to a better patient compliance. Thedispersible tablets of the present invention have a disintegration timeof less than 5 minutes or preferably less than 4 minutes. In a furtherembodiment the dispersible tablets of the present invention have adisintegration time of less than 3 minutes, preferably less than 2minutes or most preferred less than 1 minute based on the methodaccording to the European Pharmacopoeia.

According to the invention, the process for the preparation of thedispersible tablets comprises mixing the excipients of phase II (about10-20 minutes), adding it to phase I and re-mixing for the same periodof time. Phase III is then added to the powder mixture of phases I andII and mixed for about 2-5 minutes and compressed into tablets.

Phase I comprises compound I and one or more pharmaceutically acceptableexcipients which are present in a concentration of more than 5% inweight based on the total weight of the dispersible tablet.

Phase II comprises the pharmaceutically acceptable excipients which arepresent in a concentration of less than 5% in weight based on the totalweight of the dispersible tablet with the exception of the lubricants ofthe stearate type.

Phase III comprises lubricants of the stearate type.

Procedures which may be used may be conventional or known in the art orbased on such procedures e.g. those described in L. Lachman et al., TheTheory and Practice of Industrial Pharmacy, 3rd Ed., 1986; H. Sucker etal., Pharmazeutische Technologie, Thieme, 1991; Hagers Handbuch derpharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington'sPharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or latereditions.

Since compound I is practically insoluble in water, it was a surprisethat despite the general knowledge that direct compression (i.e.compression without previous wet granulation) does not enhance thedissolution of compounds with low solubility, compound I exhibits gooddissolution from the dispersible tablets of the present inventionobtained by the method of direct compression.

In fact, the dissolution of compound I from the dispersible tablets ofthe invention is such that more than 60%, especially more than 70% w/wof compound. I is dissolved within 15 minutes when tested in 900 ml ofphosphate buffer (pH=6.8) with 0.1% w/v sodium lauryl sulphate heated to37° C. and stirred at 100 rpm with a paddle as described in the UnitedStates Pharmacopoeia.

In one aspect of the invention one or more lubricants may be sprayed onthe material contacting surfaces of pressing tools, e.g. punches and/ordies, of the tabletting machine before compression.

The physical and chemical stability of the dispersible tablets may betested in conventional manner, e.g. by measurement of dissolution,friability, disintegration time, assay for compound I degradationproducts, appearance and/or microscopy, e.g. after storage at roomtemperature, i.e. 25° C./60% r.h. (relative humidity), and/or storage at40° C./75% r.h.

The dissolution rate is stable over time and different storageconditions. In a preferred embodiment the dissolution rate of thetablets is stable over at least 6 months when they are stored at 25°C./60% r.h. and 40° C./75% r.h.

The dispersible tablets may vary in shape and be, for example, round,oval, oblong, cylindrical, clover-shaped or any other suitable shape.

In a preferred embodiment of the invention dispersible tablets obtainedby the compression method described above are clover shaped or round.The edges of the dispersible tablets may be beveled or rounded. Mostpreferably, the dispersible tablets are clover shaped with bevelededges. The dispersible tablets according to the invention may be scoredor engraved.

The dispersible tablet according to the invention is preferablyclover-shaped, quadrisected with beveled edges. The dispersible tablethas a diameter ranging between 8 and 15 mm, most preferably between 9and 11 mm. Its thickness is ranging from 2.5 to 4.5 mm, preferablybetween 2.9 and 3.9 mm.

The dispersible tablets of the invention comprising about 32 mg ofcompound I as active moiety may have a hardness of from about 50 to 120N, preferably 60 to 100 N.

The dispersible tablets of the invention may be colored and/or marked soas to impart an individual appearance and to make them instantlyrecognizable. The use of dyes can serve to enhance the appearance aswell as to identify the dispersible tablets. Dyes suitable for use inpharmacy typically include carotinoids, iron oxides or chlorophyll. Thedispersible tablets of the invention may be marked using an imprintcode.

The dispersible tablets of the present invention are useful for thetreatment of PAH and exhibit a good pharmacokinetic profile. Thedispersible tablets of the present invention can be administered e.g.twice daily with an effective dosing of the active ingredient compound Iin the range of 2 mg/kg to 4 mg/kg body weight.

The tablet may be packed in any possible blister known in the art, asfor example into aluminum blisters.

As can be seen from FIG. 1, the paediatric formulation has demonstratedabsorption based on pk data.

The following non-limitative examples illustrate the invention.

EXAMPLE 1

Amount per Percent Components Tablet [mg] [w/w] Phase I Compound I as33.045 11.39 monohydrate, micronized Microcrystalline cellulose (1.1)116.265 40.09 Dicalcium phosphate (1.1) 101.500 35.00 Phase IICroscarmellose sodium (1.2) 11.600 4.00 Colloidal silicone dioxide (1.3)2.900 1.00 Tartaric acid (1.4) 7.000 2.41 Tutti Frutti (1.5) 9.000 3.10Aspartame (1.6) 3.700 1.28 Acesulfame potassium (1.6) 1.800 0.62 PhaseIII Magnesium stearate (1.7) 3.190 1.1 Total 290

Tablet Properties:

Parameter Value Diameter 10 mm Friability <0.3% Disintegration at 15-22°C. (EP) <40 secs Dissolution, mean of 6 tablets More than 75% Paddlemethod, 100 rpm, phosphate within 15 minutes buffer at pH = 6.8 with0.1% sodium lauryl sulphate, 37° C.

EXAMPLE 2

Amount per Percent Components Tablet [mg] [w/w] Phase I Compound I asmonohydrate 33.045 11.80 Microcrystalline cellulose (1.1) 135.200 48.29Dicalcium phosphate (1.1) 70.000 25.00 Phase II Croscarmellose sodium(1.2) 11.200 4.00 Colloidal silicone dioxide (1.3) 2.800 1.00 Tartaricacid (1.4) 6.250 2.23 Tutti Frutti (1.5) 9.000 3.21 Aspartame (1.6)3.700 1.32 Acesulfame potassium (1.6) 1.800 0.64 Glyceryl dibehenate(1.7) 5.600 2.00 Phase III Magnesium stearate (1.7) 1.400 0.50 Total 280

Tablet Properties:

Parameter Value Diameter 10 mm Friability <0.3% Disintegration at 15-22°C. (EP) <40 secs Dissolution, mean of 6 tablets More than 75% Paddlemethod, 100 rpm, phosphate within 15 minutes buffer at pH = 6.8 with0.1% sodium lauryl sulphate, 37° C.

EXAMPLE 3

Amount per Percent Components Tablet [mg] [w/w] Phase I Compound I asmonohydrate 33.045 15.74 Microcrystalline cellulose (1.1) 79.765 37.98Dicalcium phosphate (1.1) 63.000 30.00 Phase II Croscarmellose sodium(1.2) 8.400 4.00 Colloidal silicone dioxide (1.3) 2.100 1.00 Tartaricacid (1.4) 6.250 2.98 Strawberry (1.5) 9.000 4.29 Aspartame (1.6) 3.7001.76 Acesulfame potassium (1.6) 1.800 0.86 Phase III Magnesium stearate(1.7) 2.940 1.40 Total 210

Tablet Properties:

Parameter Value Diameter 9 mm Friability <0.3% Disintegration at 15-22°C. (EP) <40 secs Dissolution, mean of 6 tablets More than 75% Paddlemethod, 100 rpm, phosphate within 15 minutes buffer at pH = 6.8 with0.1% sodium lauryl sulphate, 37° C.

1. A dispersible tablet comprising compound I of the formula

or a pharmaceutically acceptable salt or solvate thereof, andpharmaceutically acceptable excipients.
 2. The dispersible tabletaccording to claim 1 comprising the following pharmaceuticallyacceptable excipients: a) at least one filler and b) at least onelubricant.
 3. The dispersible tablet according to claim 2 furthercomprising at least one disintegrant.
 4. The dispersible tabletaccording to any one of the preceding claims comprising at least oneacidifying agent and/or at least one flavouring agent and/or at leastone sweetening agent.
 5. The dispersible tablet according to claim 1comprising the following pharmaceutically acceptable excipients: one ormore fillers in a total amount of 40 to 85% in weight based on the totalweight of the dispersible tablet, one or more disintegrants in a totalamount of 0.5 to 20% in weight based on the total weight of thedispersible tablet, one or more glidants in a total amount of 0.1 to 5%in weight based on the total weight of the dispersible tablet, one ormore acidifying agents in a total amount of 0.5 to 13% in weight basedon the total weight of the dispersible tablet, one or more flavouringagents in a total amount of 1 to 15% in weight based on the total weightof the dispersible tablet, one or more sweetening agents in a totalamount of 0.1 to 10% in weight based on the total weight of thedispersible tablet, and one or more lubricants in a total amount of 0.05to 7% in weight based on the total weight of the dispersible tablet. 6.The dispersible tablet according to any one of the preceding claimswherein compound I is in the monohydrate form.
 7. The dispersible tabletaccording to any one of the preceding claims obtainable by using themethod of direct compression.
 8. The dispersible tablet according to anyone of claims 1 to 7 for use as a medicament.
 9. Use of compound I, or apharmaceutically acceptable salt or solvate thereof, for the preparationof a dispersible tablet according to any one of claims 1 to 7, for usein the treatment of pulmonary arterial hypertension.
 10. A process forthe preparation of a dispersible tablet according to any one of claims 1to 7, characterized in that the tablet is prepared by directcompression.